Structure‐Based Design of Benzoxazoles as new Inhibitors for D‐Alanyl – D‐Alanine Ligase

D ‐Alanyl – D ‐alanine ligase is an enzyme which catalyzes the dimerization of D ‐alanine, and, as such, has an essential role in bacterial cell wall biosynthesis. It has been shown that inhibition of D ‐alanyl – D ‐alanine ligase prevents bacterial growth. D ‐Alanyl – D ‐alanine ligase represents therefore a viable antimicrobial target. The 3D structure of this enzyme complexed with a phosphinophosphate inhibitor has been reported, which allows for structure‐based design studies. Four softwares (LUDI, MCSS, Autodock, and Glide) developed either for fragment or full‐molecule docking were compared and scored for their ability to position in the active site four prototypic ligands: two inhibitors, i.e. a phosphinophosphate derivative and D ‐cycloserine, D ‐alanine and D ‐alanyl – D ‐alanine. Best performances were obtained with Glide and MCSS. A short series of novel derivatives based on a 2‐phenylbenzoxazole scaffold was designed de novo on the basis of computational data. The best compound was found to fully inhibit the D ‐alanyl – D ‐alanine ligase of E. faecalis with an IC 50 of 400 μM.